Organ fibrosis can occur in most body tissues, including the heart and lung, and it is a serious cause of morbidity and mortality world-wide. When tissues are damaged, they can either repair normally or they can repair with scarring (after a more severe or prolonged injury). The formation of scar tissue can be debilitating and even deadly when it occurs in vital organs such as lung and heart. Sadly, there are few available therapies for cardiac and pulmonary fibrosis. Thus, a major unmet need is to understand common pathologic processes involved in driving fibrogenesis, and to develop highly effective anti-scarring treatments. The objective of this RFA is to garner information from two or more organ systems to inform our understanding of common mechanisms of disease pathogenesis and to develop new therapeutics. Our grant application focuses on cardiac and lung scarring. We have discovered novel and common feedforward loops that we propose drive fibrosis in these and other organs. Our research team has published that Lactate Dehydrogenase A (LDHA) acts as an amplifier of lung fibrosis by increasing production of lactic acid, which lowers the local pH and activates latent TGF?, a potent pro-fibrotic cytokine. Separately, we were the first to report that Myocardin-Related Transcription Factor A (MRTF-A) drives myofibroblast differentiation of cardiac fibroblasts. We now have exciting data that links these two observations. Specifically, we have identified that MRTF-A drives LDHA expression via a previously unknown CArG box in the LDHA promoter. Here, we will test our overall hypothesis that MRTF-A and LDHA act in concert to form a pro-fibrotic feed-forward loop that amplifies tissue fibrosis in multiple organs by activating latent TGF?, via lactic acid-lactate production, and that pharmacologic inhibition of this feed-forward loop represents a novel therapeutic strategy for an otherwise untreatable pathologic response. Our Specific Aims to study fibrotic mechanisms in lung and heart are as follows. Specific Aim 1. Investigate the role of lactic acid/lactate and LDHA in promoting myofibroblast differentiation of lung and cardiac fibroblasts, and in driving pulmonary and cardiac fibrosis in vivo. Specific Aim 2. Investigate the role of MRTF-A as a common amplifier of fibrosis in lung and heart. Specific Aim 3. Evaluate novel small molecule inhibitors of LDHA and the MRTF/TGF-? pathway as potential common therapeutic agents for cardiac and lung fibrosis. These studies will provide key new mechanistic data describing a novel feed-forward loop that amplifies pro-fibrotic signaling in both heart and lung. Our findings will show that MRTF-A and LDHA act together to promote fibrosis via lactic acid-mediated activation of TGF-?. We will also provide critical proof-of concept data using cell culture and preclinical animal models that inhibition of the lactate metabolic pathway is a novel and viable therapeutic target in fibrosing diseases of lung and heart.